Maintenance Therapy with Low-Dose Azacitidine (AZA) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Relapsed or Refractory AML or MDS: A Dose and Schedule Finding Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1134-1134 ◽  
Author(s):  
Marcos De Lima ◽  
Leandro de Padua Silva ◽  
Sergio Giralt ◽  
Krishna Komanduri ◽  
Borje S. Andersson ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Chronic Gvhd ◽  
Controlled Study ◽  
Unrelated Donor ◽  
Hematologic Toxicity ◽  
Dna Hypomethylation ◽  
Global Methylation ◽  
Hematopoietic Stem ◽  
Number Of Cycles ◽  
To Receive

Abstract Relapse is the major cause of treatment failure after HSCT for relapsed AML. Maintenance therapy may provide an “adjuvant’ support for the allogeneic graft-versus-leukemia effect, decreasing the likelihood of recurrence. AZA is a DNA methyltransferase inhibitor that induces DNA hypomethylation, leading to leukemic cell differentiation and potentially increased tumor immunogenicity. FDA approved doses are however unlikely to be tolerated due to myelosuppression. We hypothesized that AZA will reduce relapse rates, and designed a phase I clinical trial to determine the safest dose and schedule combination. Methods. Eligible were patients (pts) with AML/MDS not in 1st complete remission (CR), not candidates for ablative regimens due to age or comorbidities. Conditioning regimen was gemtuzumab ozogamicin 2 mg/m2, fludarabine 120mg/m2, and melphalan 140mg/ m2. GVHD prophylaxis was tacrolimus/mini-methotrexate (ATG in unrelated donor HSCT). We investigated 4 AZA doses: 8, 16, 24 and 32 mg/m2 SQ daily x 5 starting on day +42, given for 1–4 28-day cycles (schedule). An outcome-adaptive method was used to determine dose and schedule (number of cycles): pts were assigned to a dose/ schedule combination on the basis of the data (organ/hematologic toxicity) from all pts treated previously in the trial. Pts in CR on transplant day+30, with donor chimerism, no grade III/IV GVHD, platelet >10,000/mm3 and ANC >500/mm3 were eligible to receive AZA. Methylation status of long interspersed nuclear elements (LINE) was analyzed by pyrosequencing as a surrogate marker of global DNA methylation (figure). Results. 80 pts were transplanted; 44 (56%) were eligible to receive AZA: 2 refused; 42 pts. (4 too early) received it. Table shows pts characteristics. 88 cycles were delivered at 8 (n=7), 16 (n=5), 24 (n=21) and 32 mg/m2 (n=9). AZA-associated/possibly associated toxicities were grade (gd) I/II or III thrombocytopenia (n=5; n=2), gd I nausea (n=5), gd II fatigue (n=2), gd III transaminase elevation (n=1, AZA + posaconazole), conjunctival erythema (n=1), pruritus (n=1), gd I confusion (n=2), retina hemorrhage (possibly pre-existing), gd II creatinine elevation (n=1), oral ulcers (n=1), papilledema (n=1), and pulmonary hemorrhage (n=1; second HSCT, fungal pneumonia/hepatic VOD during the 1st AZA cycle, evolving with thrombocytopenia/bleeding). Reversible thrombocytopenia was more frequent at 32 mg/m2. Infections: bacteremia, n=5; respiratory, n=6; parainfluenza, n=2, CMV reactivation, n=6. Most pts were 100% donor chimeras at the start of AZA. AZA did not affect GVHD incidence (table). 10 pts have relapsed, 3 while on AZA 16 or 24 mg/m2. Median follow-up is 13 months (3–31; n=26). 12 pts have died, 8 of recurrence, 2 of GVHD, 1 of pneumonia and 1 of unknown causes. Day +100 non-relapse mortality was 6 %; 4 pts died within the first 100 days post HSCT due to relapse (n=2), pneumonia (n=1), and GVHD (n=1). Actuarial 1-year event-free and overall survival is 58% and 72%. No dose was found to significantly affect global methylation (gene specific methylation studies are ongoing). The trial has reached the dose 32 mg/m2 and the projected maximum number of cycles. Thrombocytopenia prevented escalation to the next level (40 mg/m2). Variables N (%) (range) Age: median (range) 60 (24–67) Median number of previous chemotherapy regimens 2 (0 – 5) Cytogenetics Good / Intermediate / bad 1 (3%)/ 22 (58%)/ 15(39%) Previous Allogeneic SCT 7 (18%) Disease status at transplant CR2/CR3 8/2 (26,3%) First Relapse/induction failure 12/13 (66,7%) ≥ second/third relapse 3 (7%) Charlson Comorbidity Index score 0 / 1 4 (10,5%) / 4 (10,5%) 2 / 3 5 (13,2%) / 7 (18,4%) >3 18 (47.4%) Donor type Sibling/unrelated 23/15 (58/42%) Cells Source:PB/BM 73% / 27% Grade II/III Acute GVHD Grade 2 / grade 3 6 (16,7%) / 4 (11%) Chronic GVHD 14 (46,5%) Conclusion. AZA 32 mg/m2 is safe and can be administered for at least 4 cycles to heavily pre-treated pts. with comorbidities. The safety profile indicates that longer periods of administration should be investigated. We will initiate a randomized, controlled study of AZA for one year versus best standard of care (no maintenance therapy) for similarly highrisk patients with AML/MDS. Figure Figure

A Dose and Schedule Finding Study of Maintenance Therapy with Low-Dose 5-Azacitidine (AZA) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for High-Risk AML or MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3012-3012 ◽  
Author(s):  
Marcos de Lima ◽  
L. Padua ◽  
S. Giralt ◽  
C. Hosing ◽  
K. Komanduri ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Methylation Status ◽  
Surrogate Marker ◽  
Unrelated Donor ◽  
Dna Hypomethylation ◽  
Global Methylation ◽  
Hematopoietic Stem ◽  
Number Of Cycles

Abstract Disease relapse is the most frequent cause of treatment failure after HSCT in patients (pts) with refractory AML/MDS. AZA inhibits the enzyme DNA methyltransferase and leads to DNA hypomethylation. It may induce leukemic cell differentiation and increased immunogenicity, therefore potentially magnifying the graft-versus-leukemia effect. Lower doses are likely to be better tolerated after HSCT and to be as effective as larger doses in inducing hypomethylation. We hypothesized that AZA maintenance will result in lower relapse rates, and designed a phase I clinical trial to determine the safest dose and schedule combination. We also monitored global methylation post HSCT as a surrogate marker for changes in methylation status during AZA. Methods: Pts with AML or high-risk MDS not in 1st complete remission (CR), not candidates for ablative regimens were eligible. Conditioning regimen was gemtuzumab ozogamicin 2 mg/m2 (day -12), fludarabine 120mg/m2, and melphalan 140mg/m2. GVHD prophylaxis was tacrolimus/mini-methotrexate. ATG was administered to recipients of unrelated donor (UD) HSCT. We investigated 3 AZA doses: 8, 16, and 24 mg/m2 daily × 5 starting on day +42, and given for 1–4 28-day cycles (schedule). An outcome-adaptive method was used in order to determine both dose and schedule (number of cycles): pts were assigned to a dose/schedule combination chosen on the basis of the data (toxicity) from all pts treated previously in the trial. Patients in CR on transplant day +30, without gd III/IV GVHD, platelet >10,000/mm3 and ANC >500/mm3 were eligible to receive SQ AZA. The methylation status of long interspersed nuclear elements (LINE) was analyzed by pyrosequencing and used as a surrogate marker of global DNA methylation in mononuclear cells of 22 pts(55%) that received AZA for at least 1 cycle. Results: 40 patients were enrolled; median age was 57 years (22–72). Diagnoses were MDS with high IPSS(n=6) and AML (n=34). Disease status at HSCT: complete remission (CR), 10% (n=4); chemo-naive MDS, 2% (n=1); induction failure, 35% (n=14), 1st/2nd relapse, 42.5% (n=21). Patients had received a median of 5 courses of chemotherapy (0–23) prior to HSCT, and the median comorbidity Charlson score was 3 (0–8). Donors were related (n=23) or UD(n=17), and stem cell source was bone marrow(n=8) or peripheral blood(n=32). Median follow-up of alive pts is 11 mo (2.5–20; n=21). 49 cycles of AZA were delivered at 8 (n=7 pts), 16 (n=4) and 24 mg/m2 (n=12 pts). AZA-associated toxicities were grade I/II hematologic, nausea and fatigue. There was no increase in GVHD: gd II-IV aGVHD, and chronic GVHD rates were 34% and 30%. 11 pts have relapsed, 2 while on AZA (16 and 24 mg/m2). Day +30 and +100 non-relapse mortality was 5% and 12%. Mean LINE methylation results were as follows: baseline: 43.51% (±5; n=22); on cycle 1, 5th day of AZA: 24 mg/m2=43.58% (±5; n=9); 16 mg/m2: 36.93% (±6.5; n=4); 8 mg/m2: 42.86% (±5; n=3). There were trends towards lower levels of global methylation at 16mg/m2 in subsequent cycles. The trial design has reached the higher dose and the maximum number of cycles given the absence of AZA-related major toxicities. Conclusion: AZA at 24 mg/m2 is safe and can be administered for at least 4 cycles. The lack of toxicity and the methylation studies indicate that higher doses and longer periods of administration should be investigated.

Maintenance Therapy With Decitabine After Allogeneic Hematopoietic Stem Cell Transplantation For Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4638-4638 ◽  
Author(s):  
Iskra Pusic ◽  
Jaebok Choi ◽  
Noel Bernabe ◽  
Camille N. Abboud ◽  
Peter Westervelt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
To Receive ◽  
Acute Myeloid

Introduction Disease recurrence is the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after alloHSCT. Decitabine (DAC) is a hypomethylating agent that irreversibly binds to and inhibits DNA methyltransferase-1, leading to loss of DNA methylation. DAC maintenance may help eradicate minimal residual disease and facilitate a graft-versus-leukemia effect. Lower DAC doses are expected to be better tolerated after alloHSCT and equally effective in promoting hypomethylation. Additionally, DAC maintenance may have a favorable effect on the incidence of GVHD by enhancing the effect of T-regulatory lymphocytes (Choi et al, Blood, 2012). Methods Patients (pts) with AML/MDS in complete remission (CR) after alloHSCT, with ANC> 1,500/mm3, platelets> 50,000/mm3, and without grade III-IV acute GVHD were eligible to receive DAC, starting between day +50 and +100 after alloHSCT. We investigated 4 DAC doses: 5, 7.5, 10 and 15 mg/m2/day IV x 5 days of a 6-week cycle, for a total of 8 cycles. Each cohort contained 4-8 evaluable patients. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which< 20% of patients experience hematologic or non-hematologic dose limiting toxicities (DLT) during the 1st cycle of treatment. GVHD prophylaxis was at the physician discretion. Results 19 pts were enrolled to date; the median age was 60 y (22-66); 14 pts had AML and 5 MDS. All conditioning regimens were myeloablative; 14 donors were unrelated and 5 related. 3 cohorts have been completed and a final 4th cohort is currently enrolling. Median follow-up from alloHSCT is 24 mo (7-36). 8 pts (44%) completed all 8 cycles: 7 pts remain in CR with stable counts and full donor chimerism and 1 pt developed CNS-only relapse 26 mo after alloHSCT. 9 pts went off study before cycle 6: 1 pt for poor compliance after 6 cycles, 3 pts for relapsed disease (after 1, 2 and 5 cycles, respectively), 2 pts for sepsis, and 2 pts after physician decision. 6 pts have died: 3 from relapse, 2 from sepsis after 3 cycles of DAC (they were not neutropenic at a time), and 1 form sepsis >1 y after getting off study. 2 pts are still on study passed 3rd cycle. DAC maintenance was well tolerated. Associated hematological toxicities were mostly grade I/II leukopenia and thrombocytopenia. There was one occurrence of hematological DLT. No MTD has been reached. Non-hematological toxicities were grade I/II nausea, fatigue, neuropathy, and transaminase elevation. 2 pts had grade I-II acute GVHD prior to starting DAC and both resolved while on DAC; 1 pt developed grade IV gut GVHD coinciding with first cycle of DAC that completely resolved on DAC; 1 pt developed late acute GVHD of skin and liver around 6th cycle of DAC that resolved after few wks. 2/8 pts who completed 8 cycles of DAC developed very mild skin and oral chronic GVHD not requiring any systemic therapy, 1/8 pt developed late acute GVHD responding to therapy, and 1 pt developed overlap GVHD syndrome. 4/7 pts who went off study prior cycle 6, and did not have an early relapse, developed severe chronic GVHD requiring intensive immunosuppressive therapy. Conclusion To our knowledge this is the first report of DAC as maintenance therapy after alloHSCT. DAC at the dose of 15 mg/m2 for 5 days every 6 weeks is safe and can be administered in heavily pretreated pts in the post-alloHSCT setting. Approximately 43% of pts were able to receive all 8 cycles. The lack of toxicities and low incidence of GVHD indicate that a longer period of administration should be investigated. Although there is a trend of increased FOXP3 expression, results were not statistically significant. Further correlative studies, including genome-wide methylation studies, are ongoing. Disclosures: Off Label Use: Decitabine maintenance after alloHSCT.

Results of an AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Randomized Clinical Trial in Children with Low- and Intermediate-Risk Relapsed Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 65-65
Author(s):  
Franco Locatelli ◽  
Marco Zecca ◽  
Gianni Cazzaniga ◽  
Luciana Vinti ◽  
Andrea Biondi ◽  
...  
Keyword(s):  
T Cell ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Continuous Treatment ◽  
Unrelated Donor ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Line Therapy ◽  
To Receive

Abstract Leukemia recurrence remains the main cause of treatment failure in children with ALL. The prognosis of children with relapsed ALL is strongly influenced by the site of relapse, time elapsing between diagnosis and recurrence and by blast cell immune-phenotype. Recently, several groups reported probabilities of disease-free survival (DFS) in the order of 60% for children with low/intermediate-risk ALL in 1st relapse using different approaches. Despite this remarkable progress, the best re-induction and consolidation treatment remains to be defined. We, thus, conducted from 10/2003 to 06/2012 a multicenter randomized trial aimed at comparatively evaluating the efficacy of 2 alternative approaches in centers affiliated to the Italian AIEOP network. Included in the study were patients below the age of 18 experiencing late (i.e. more than 6 months from treatment discontinuation) isolated extramedullary (IEM) relapse (S1 patients, #22) or children with B-cell precursor (BCP)-ALL who had early (i.e. between 18 months from diagnosis and 6 months after completion of front-line treatment) or late combined bone marrow (BM) relapse, late isolated BM relapse of BCP–ALL, and very early (i.e. within 18 months from diagnosis) or early IEM of either BCP-ALL or T-cell ALL (S2 patients, # 255). S2 children were randomized to receive induction therapy consisting of either two multiagent chemotherapy courses, F1 and F2 (ARM-A), according to the ALL-REZ BFM P95/96 trial, or a classical 4-drug continuous reinduction therapy (protocol I-A-IDA, ARM-B). After induction, ARM-A patients were given a continuous treatment element including idarubicin (Protocol II-IDA), followed by 5 additional alternating R1/R2 courses and maintenance therapy (24 months). After induction therapy, ARM-B patients received 8 additional alternating R1/R2 courses and maintenance therapy (24 months, see Figure 1). S1 patients received ARM-A treatment with the exception of only 3 alternating R1/R2 consolidation courses and shorter maintenance therapy (12 months). All S2 children with an available HLA-identical sibling were candidate to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT), while those relapsing within 48 months from diagnosis were eligible to receive the allograft also from an unrelated donor (UD) of BM cells or a suitable UD cord blood unit. For S1 patients, both autologous (auto) and allo-HSCT were considered acceptable post-remissional options; auto-HSCT was also employed in a minority of S2 children relapsing more than 48 months from diagnosis. Of the whole cohort of children, 143 were males and 134 were females; median age at diagnosis and at time of relapse was 5 (range 0.2-17) and 9 (range 1.1-17.9) years, respectively. Among the 255 S2 patients, 127 were allocated to ARM-A and 128 to ARM-B. All S1 children obtained a 2nd complete remission (CR), while the probability of reaching 2nd CR of S2 patients was similar in the 2 randomization arms (95% vs 96%). The 6-year DFS for the 22 S1 children was 75% (confidence interval, CI, 55-94); 13 of these children were given either auto-HSCT (#7) or allo-HSCT (#6), while 9 were treated with chemotherapy only. The 6-year DFS for the 255 S2 children was 65% (CI 57-72); the DFS for ARM-A and ARM-B patients was 60% (CI 48-71) and 69% (CI 60-79), respectively (p=ns). Among S2 patients, 179 received allo-HSCT either from an HLA-identical sibling (#51) or a BM/CB UD (#105) or an HLA-partially matched relative (#23) after T-cell depletion of the graft (TCD haplo-HSCT). Of the remaining 76 children, 12 were given auto-HSCT, while 64 received chemotherapy only. The 6-year DFS for S2 children who did or did not receive allo-HSCT was 66% (CI 58-74) and 58% (CI 38-77), respectively (p=ns). Among allo-HSCT recipients, the 6-year DFS was 59% (CI 42-75), 72% (CI 62-82) and 62% (CI 41-83) for children given HLA-identical sibling, UD or TCD haplo-HSCT, respectively (p=ns). Altogether, these results confirm that a high proportion of children with low-/intermediate-risk relapsed ALL can be rescued by second line therapy, including transplantation. A re-induction course similar to that employed in first-line therapy is as effective as that proposed in the ALL-REZ BFM P95/96 trial. UD-HSCT and TCD haplo-HSCT are suitable and effective alternatives for children candidate to an allograft but lacking an HLA-identical sibling. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) in Children with Acute Leukemia: Risks and Benefits of Umbilical Cord Blood (CB) Versus HLA A, B, C, DRB1 Allele-Matched Bone Marrow (BM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 434-434 ◽  
Author(s):  
Mary Eapen ◽  
Pablo Rubinstein ◽  
Mei-Jie Zhang ◽  
Cladd Stevens ◽  
Joanne Kurtzberg ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
High Cell ◽  
Hematopoietic Stem ◽  
Drb1 Allele ◽  
Cell Dose ◽  
Grade 3 ◽  
To Receive

Abstract CB has proven to be an acceptable alternative to BM for transplantation. However, it is unknown how CB mismatched at HLA 0–2 loci compares to HLA matched BM. Therefore, we compared results observed in 503 recipients of CB with those in 116 recipients of allele-matched BM (at HLA A, B, C, DRB1). Of CB recipients, 35 were matched at HLA A, B (antigen-level) and DRB1 (allele-level), 201 were mismatched at 1-locus and 267 were mismatched at 2-loci. All patients (aged &lt;16 years) had acute leukemia and were transplanted between 1995–2003. Median follow up was 45 and 59 months for CB and BM recipients, respectively. Compared to recipients of allele-matched BM, CB recipients were younger, non-Caucasian, more likely to have advanced disease at HSCT, less likley to receive radiation and somewhat more likely to receive cyclosporine. Leukemia-free survival (LFS) rates was superior in recipients of HLA matched CB (p=0.040). Notably LFS and overall survival (OS) at 5-years were comparable between those receiving allele-matched BM and 1 or 2-loci mismatched CB. These results in LFS and OS are in part explained by differences in risks of transplant-related mortality (TRM) and relapse between patient populations. Compared to allele-matched BM transplants, TRM was similar in recipients of matched and 1-locus mismatched/high cell dose (&gt;0.3 x 108/kg) CB and higher in recipients of 1-locus mismatched/low cell dose (≤0.3 x 108/kg) and 2-loci mismatched CB (any cell dose) (p=0.005, p&lt;0.001, respectively). Conversely, relapse rates were lower in recipients of CB mismatched at 1 or 2-loci (p=0.037, p=0.003, respectively). As previously observed, probability of neutrophil recovery (≥500/ul) at day 42 depended on graft type, HLA-match and cell dose (98% with BM; 85% with matched CB; 79% with 1 or 2-loci mismatched CB/high cell dose; 64% with 1 or 2-loci mismatched CB/low cell dose). Compared to allele-matched BM, risks of grade 2–4 and and grade 3–4 acute GVHD were lower after matched CB (relative risk [RR] 0.45, p=0.035, RR 0.51, p=0.035, respectively) and similar after mismatched CB. Risks of chronic GVHD were lower after matched or mismatched CB transplants (RR 0.66, p=0.036). The Table below shows the 5-year probabilities of TRM, relapse, LFS and OS by graft type. These results are the first to support the use of HLA matched or mismatched CB grafts with an adequate cell dose as first line transplant treatment regardless of the availability of a HLA allele-matched BM donor in the setting of actue leukemia in those &lt;16 years. TRM Relapse LFS OS BM, allele-matched at A, B, C, DRB1 19% 41% 38% 45% CB, A, B antigen-matched, DRB1 allele-matched 6% 34% 60% 63% CB, 1-locus mismatched, high cell dose 29% 31% 41% 45% CB, 1-locus mismatched, low cell dose 43% 21% 37% 36% CB, 2-loci mismatched, any cell dose 49% 20% 33% 33%

Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 473-476 ◽  
Author(s):  
Maria Ester Bernardo ◽  
Eugenia Piras ◽  
Adriana Vacca ◽  
Giovanna Giorgiani ◽  
Marco Zecca ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Hematopoietic Stem

Abstract Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

Outcome of Patients Developing GVHD after DLI for CML Relapse from HLA-Identical Sibling or VUD HSCT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1817-1817
Author(s):  
Yves Chalandon ◽  
Christoph Schmid ◽  
Kimmo Porkka ◽  
Alvaro Urbano-Ispizua ◽  
Bernd Hertenstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Median Number ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Initial Cell ◽  
Cell Dose ◽  
Stem Cell Source ◽  
Related Mortality

Abstract Using data submitted to the EBMT registry, we analyzed outcome on 344 patients (pts) who had received donor lymphocyte infusions (DLI) for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) in 31 centers. 113/344 pts (33%) developed acute graft-versus-host disease (aGVHD) a median of 50 days post DLI (max grade: I=42, II=30, III=31, IV=6)(60% grade II–IV). Organs involved (%): skin (88), liver (42), gut (30). Median age was 38 (4–59), 58% pts were male, 62 transplants were HLA-identical sibling and 51 unrelated. 74 were T-cell depleted, 92 transplanted in CP1, 21 beyond CP1. Relapse was molecular in 19 pts, cytogenetic in 31, hematological in 49, accelerated or blastic in 12. Median initial cell dose was 107CD3+ cells/kg (0.01–32), median number of DLI was 1 (1–10). aGvHD was treated with prednisone in 92% of pts, CSA in 52 %, ATG and monoclonal antibodies in 2% and other in 19%. aGVHD resolved in 53% of the pts within a median of 63 d (7–546). 82/344 pts (24%) had chronic GVHD (cGVHD)(30 limited, 50 extensive, 2 not specified), of those 46 (56%) following aGVHD post DLI. Organs involved (%): skin (75), liver (35), lungs (13), mouth (43), eyes (22) and gut (5). Median age was 35 (6–58), 51% were male, stem cell source was PB in 15% and marrow in 85%, 43 underwent HLA-identical sibling HSCT and 39 unrelated donor HSCT. Forty-three were T-cell depleted, 66 transplanted in CP1, 16 beyond CP1. Relapse was molecular in 21 pts, cytogenetic in 29, hematological in 22, accelerated or blastic in 7. Median initial cell dose was 107 CD3+ cells/kg (0.05–40), median number of DLI was 1 (1–7). 61 pts are alive with a median follow-up of 50 mth. Treatment was with steroids in 83% of pts, CSA in 58 %, MMF in 20%, thalidomide in 15%, photopheresis in 15%, PUVA in 10% and other in 17%. cGVHD resolved in 39% of the pts within a median of 354 d (44–1588). The estimated 5-y OS post-DLI was significantly lower in pts who developed aGVHD post-DLI, 61 ± 10% vs 74 ± 7% in the one that did not, p=0.007 and also a tendency to have a lower 5-y EFS, 58 ± 10% vs 65 ± 7%, p=0.19. Median duration of response to DLI in aGVHD pts was 4 y. aGVHD post-DLI did not influence the relapse rate (5 ± 5% vs 6 ± 5% in the absence of aGVHD). 5-y DLI related mortality was significantly higher in aGVHD pts, 31 ± 8% vs 4 ± 4%, p<0.00001. On the other hand, pts that developed cGVHD post-DLI had a tendency to have a better 5-y OS and EFS, 74 ± 11% and 71 ± 11% respectively vs 69 ± 6% and 62 ± 7% in those that did not, p=0.32 and 0.09. This was related to a tendency to lower incidence of relapse, 2 ± 3% in pts with cGVHD vs 9 ± 6% without, p=0.2. DLI related mortality was not different, 11 ± 8% vs 10 ± 5%, p=0.77. aGVHD post-DLI for CML relapse is mainly of advanced stage and negatively influence OS and EFS with a higher DLI related mortality. cGVHD post-DLI is mainly extensive, but pts with cGHVD tend to have better outcome with better 5-y OS, EFS and less relapse than those without, although this was not statistically significant.

Outcomes of c Hematopoietic Stem Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed, Refractory, or Transformed Indolent Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3124-3124 ◽  
Author(s):  
Andrew R. Rezvani ◽  
Brenda M. Sandmaier ◽  
Barry Storer ◽  
Michael Maris ◽  
Edward Agura ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Aggressive Lymphoma ◽  
Optimal Timing ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hct ◽  
Grade 3

Abstract Sixty-two patients (pts) with chemotherapy-refractory indolent or transformed NHL were treated at 10 centers with allogeneic HCT from related (n=34) and unrelated (n=28) donors after 2 Gy total body irradiation with or without fludarabine. Diagnoses included follicular lymphoma (FL) (n=54, including 10 with grade 3 FL), small lymphocytic lymphoma (n=6), and marginal zone lymphoma (n=2). Median age was 54 years (range 33–66 years), and median time from diagnosis to HCT was 4.4 years (range 0.5–18.5 years). Sixteen pts had histologically documented transformation to diffuse aggressive lymphoma prior to HCT. Twenty-seven pts (44%) had failed autologous HCT. Disease status at the time of HCT was complete response (CR, n=16), partial response (PR, n=22), refractory (n=13), untested relapse (n=9), or unknown (n=2). Eleven of the 28 unrelated donor/recipient pairs (39%) had HLA mismatches: 2 at a single allele, 7 at a single antigen, and 2 at an antigen and an allele. One pt had non-fatal graft rejection from a 1-antigen-mismatched unrelated donor. Median follow-up of survivors after HCT was 36.6 months (range 2.3–60 months). Responses (CR [n=18] and PR [n=7]) were seen in 25 of 44 (57%) pts with evaluable disease prior to HCT, while 5 had stable disease, 9 progressed, and 5 were not evaluable due to early non-relapse mortality (NRM) on d27–d108. Two of 16 pts (13%) transplanted in CR relapsed; one was treated with donor lymphocyte infusion and achieved a persistent CR. The incidences of acute GVHD grades II–IV, III–IV, and chronic GVHD were 63%, 19%, and 53%, respectively. At 3 years, the risks of relapse/progression and NRM were 19% and 42%, respectively. There was a trend toward increased mortality with unrelated donors (HR 1.87 [0.9–3.7, p=0.08]). Progression-free and overall survival (PFS and OS) were significantly better in the non-transformed group (see tables 1 and 2). Table 1. Outcomes Non-transformed Transformed Relapse 6/46 (13%) 6/16 (38%) NRM 20/46 (43%) 6/16 (38%) 3-year OS 24/46 (52%) 4/16 (25%) 3-year PFS 20/46 (43%) 4/16 (25%) Table 2. Hazard Ratios (HR) for Transformed vs. Non-Transformed Pts HR (95% CI) p All-cause Mortality 2.39 (1.2–4.9) 0.02 Relapse/progression 4.75 (1.5–15) 0.01 Grade 3+ acute GVHD 1.84 (0.5–6.3) 0.35 Extensive chronic GVHD 1.96 (0.8–5.0) 0.18 Figure Figure Allogeneic HCT after non-myeloablative conditioning can produce durable responses and prolonged survival in pts with refractory indolent or transformed NHL. Pts transplanted before histologic transformation had significantly better outcomes. Future efforts will focus on reducing NRM and identifying optimal timing of HCT.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

Allogeneic Bone Marrow Transplantation From HLA Mismatched Family Donors in Children with Aplastic Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 831-831 ◽  
Author(s):  
Hideki Muramatsu ◽  
Hiromasa Yabe ◽  
Ryoji Kobayashi ◽  
Akira Kikuchi ◽  
Kazuko Kudo ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Secondary Malignancy ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Unrelated Donors ◽  
Related Donor ◽  
Family Donor

Abstract Abstract 831 The first-line therapy for children with severe aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-matched family donor, and immunosuppressive therapy (IST) is indicated for patients without HLA-matched family donors. While the standard therapy for children who fail to respond to IST is allogeneic HSCT from an HLA-matched unrelated donor, HSCT from an HLA-mismatched family donor has also been indicated. Compared with unrelated donors, an HLA-mismatched family donor has some advantages especially for children who need urgent transplantation. We analyzed the clinical outcome of 578 children (325 boys and 253 girls) with AA (age, <20 years) who received allogeneic BMT between 1990 and 2009 in Japan, and registered to the Transplant Registry Unified Management Program (TRUMP). The median age at transplantation was 11 years (0–19), and the donors were serological 6/6 HLA-matched related donors (MRD) (n = 312), 1 locus-mismatched related donor (1MMRD) (n = 44), 2–3 loci-mismatched related (haploidentical) donors (n = 9), and HLA-matched unrelated donors (MUD) (n = 213). Causes of deaths were as follows: acute graft-versus-host disease (GVHD) (n = 4), chronic GVHD (n = 4), acute respiratory distress syndrome (n = 2), severe hemorrhage (n = 7), engraftment failure (n = 5), infection (n = 18), idiopathic pneumonia (n = 8), organ failure (n = 19), secondary malignancy (n = 4), and others (n = 4). The probability of severe acute GVHD (grade III–IV) in patients transplanted from 1MMRD (26.9% ± 7.4%) was significantly higher than that in patients transplanted from MRD (4.9% ± 1.3%) (p < 0.001). The probability of 5-year overall survival (5y OS) of patients transplanted from 1MMRD (93.1% ± 3.9%) was comparable to that of patients transplanted from MRD (93.1% ± 1.5%) (p = not significant, NS), but it was significantly better than that of patients transplanted from haploidentical donors (66.7% ± 15.7%, p =.016) and MUD (79.0% ± 2.9%, p =.014). In the subgroup analysis of 1MMRD, no significant difference was observed between HLA class I-mismatched (n = 32) and class II-mismatched patients (n = 12) (5y OS; 93.8% ± 4.3% vs. 91.7% ± 8.0%, p = NS). Comparison of the survival outcome based on the transplant period (1990–1999 vs. 2000–2009) revealed that the probability of 5y OS of patients transplanted from 1MMRD was not significantly different (92.3% ± 5.2% (n = 26) vs. 94.4% ± 5.4% (n = 18), p = NS), while that of patients transplanted from MUD significantly improved in the same period as we reported previously (67.1% ± 5.5% (n = 73) vs. 86.1% ± 3.1% (n = 140), p =.001)(Yagasaki et al., Blood 2011). In multivariate analysis, haploidentical donors (p <.001), MUD (p <.001), age ≥ 10 years (p <.001), and transplant period (1990–1999 vs. 2000–2009, p =.006) were identified as independent covariates associated with unfavorable OS. In summary, our analysis revealed that an HLA-mismatched related donor, especially 1MMRD, could be selected as a donor candidate for children with AA who need urgent transplantation. Disclosures: No relevant conflicts of interest to declare.

Favorable Results of Allo-HSCT from MRD in Patients with Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5934-5934
Author(s):  
Miroslaw Markiewicz ◽  
Monika Dzierzak-Mietla ◽  
Patrycja Zielinska ◽  
Agata Wieczorkiewicz-Kabut ◽  
Sylwia Mizia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Collagen Type ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Graft Loss ◽  
Chronic Phase ◽  
Curative Treatment ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Introduction: Myelofibrosis (MF), chronic myeloid malignancy associated with shortened survival, in majority of patients develops de novo as Primary MF, but also polycythemia vera (PV) or essential thrombocythemia (ET) may progress into post-PV or post-ET MF. Although management of MF includes several treatment options, the only potentially curative treatment approach in MF is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Aim of this study was to evaluate the results of allo-HSCT in patients with MF treated in Katowice, Poland. Material and Methods: 27 pts (14 male and 13 female) with median age 51 years (range 21–63) were treated with allo-HCT due to PMF (20), post-PV (4) or post-ET (3) MF. 11,7,11,26 and 41% of pts had DIPSS 0,1,2,3 and 4, respectively. Median bone marrow cellularity was 70% (10-100%), fibrosis was collagen-type (14 pts including 2 with osteosclerosis), reticulin (10) or it was not specified (3). Splenomegaly was present in all pts: 13-20 cm (14 pts), > 20 cm (13 pts). JAK2V617F point mutation was present in 18 pts. Karyotype was available in 14 pts: in 9 normal, in 5 with variable abnormalities. Median time from diagnosis to allo-HCT was 1.5 (0.4–9.5) years. 16 pts (59.3%) received cells from HLA-matched related donor (MRD), 11 pts (40.7%) from unrelated donor: 10/10 (9) or 9/10 (2) HLA-A,B,C,DR,DQ alleles matched. Reduced intensity conditioning (RIC) was used in 26 pts, 1 patient received myeloablative conditioning (MC). Sources of stem cells were: peripheral blood (21), bone marrow (4) and both (2). All pts but one had chronic phase of MF at time of transplantation. Results: 14/27 (52%) pts are alive at median 3.4 (0.4-5.4) years after allo-HSCT: 11/16(69%) from MRD and 3/11(27%) from MUD, p=0.032. Graft failure, graft loss or PRCA were observed in 3, 5 and 1 pt, respectively. Absolute neutrophil count >0.5×109/L and platelet count >50×109/L were achieved at median 16 and 28 days, respectively. 12/27 (44%) pts reached complete blood count of Hb>10 g/dl, Plt>100 G/l and WBC>3.5 G/l; 11 of them (92%) are alive. 6/27 (22%) pts remained either RBC or PLT transfusions dependent post-transplant; 3 of them (50%) died. 9/27 (33%) pts remained both RBC and PLT transfusion dependent and all of them died. JAK2V617F mutation was completely eradicated in 11/16 evaluated previously positive patients (69%), decreased in 4 (25%) and stable in 1(6%) pt. Acute graft-versus-host disease (aGVHD) III-IV developed in 5/27 (19%) and extensive chronic GVHD in 5/19 (26%) pts. Relapse occurred in 4 pts and was treated with subsequent second transplant (in 1 pt thereafter by 3-rd allo-HSCT). Spleen length decreased at median by 5 (0.3-9.2) cm. Out of 7 pts with initial collagen fibrosis who were evaluated post-transplant, 1 had no fibrosis, 5 reticulin type and only in 1 pt collagen fibrosis was stable. Out of 3 pts with initial reticulin fibrosis it disappeared in 2 and progressed to collagen type in 1. Causes of death were GVHD (5 pts: 3 aGVHD, 2 cGVHD) and pancytopenia with either infection (7 pts) or CNS hemorrhage (1 pt). Conclusions: Allo-HSCT, the only curative treatment of myelofibrosis, provides chance of long survival, regression of the disease (lower stage of fibrosis, JAK2V617F eradication) and improved quality of life (transfusion independency, decreased splenomegaly). Transfusion independency may indicate good outcome. Favorable results are observed after allo-HSCT from MRD. Disclosures No relevant conflicts of interest to declare.

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